Carvedilol-responsive microRNAs, miR-199a-3p and -214 protect cardiomyocytes from simulated ischemia-reperfusion injury

Kyoung Mi Park, Jian Peng Teoh, Yongchao Wang, Zuzana Broskova, Ahmed S. Bayoumi, Yao Liang Tang, Huabo Su, Neal Lee Weintraub, Il-man Kim

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

The nonselective β-adrenergic receptor antagonist (β-blocker) carvedilol has been shown to protect against myocardial injury, but the detailed underlying mechanisms are unclear. We recently reported that carvedilol stimulates the processing of microRNA (miR)-199a-3p and miR-214 in the heart via β-arrestin1-biased β 1 -adrenergic receptor (β 1 AR) cardioprotective signaling. Here, we investigate whether these β-arrestin1/ β 1 AR-responsive miRs mediate the beneficial effects of carvedilol against simulated ischemia/reperfusion (sI/R). Using cultured cardiomyocyte cell lines and primary cardiomyocytes, we demonstrate that carvedilol upregulates miR-199a-3p and miR-214 in both ventricular and atrial cardiomyocytes subjected to sI/R. Overexpression of the two miRs in cardiomyocytes mimics the effects of carvedilol to activate p-AKT survival signaling and the expression of a downstream pluripotency marker Sox2 in response to sI/R. Moreover, carvedilol-mediated p-AKT activation is abolished by knockdown of either miR-199a-3p or miR-214. Along with previous studies to directly link the cardioprotective actions of carvedilol to upregulation of p-AKT/stem cell markers, our findings suggest that the protective roles of carvedilol during ischemic injury are in part attributed to activation of these two protective miRs. Loss of function of miR-199a-3p and miR-214 also increases cardiomyocyte apoptosis after sI/R. Mechanistically, we demonstrate that miR-199a-3p and miR-214 repress the predictive or known apoptotic target genes ddit4 and ing4, respectively, in cardiomyocytes. These findings suggest pivotal roles for miR-199a-3p and miR-214 as regulators of cardiomyocyte survival and contributors to the functional benefits of carvedilol therapy.

Original languageEnglish (US)
Pages (from-to)H371-H383
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume311
Issue number2
DOIs
StatePublished - Aug 2016

Fingerprint

Reperfusion Injury
MicroRNAs
Cardiac Myocytes
Adrenergic Receptors
carvedilol
Up-Regulation
Adrenergic Antagonists
Wounds and Injuries
Reperfusion
Cultured Cells
Stem Cells
Ischemia
Apoptosis
Cell Line

Keywords

  • Apoptosis
  • Heart disease
  • MicroRNAs
  • β-arrestin-biased β-adrenergic receptor signaling
  • β-blocker

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Carvedilol-responsive microRNAs, miR-199a-3p and -214 protect cardiomyocytes from simulated ischemia-reperfusion injury. / Park, Kyoung Mi; Teoh, Jian Peng; Wang, Yongchao; Broskova, Zuzana; Bayoumi, Ahmed S.; Tang, Yao Liang; Su, Huabo; Weintraub, Neal Lee; Kim, Il-man.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 311, No. 2, 08.2016, p. H371-H383.

Research output: Contribution to journalArticle

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AU - Broskova, Zuzana

AU - Bayoumi, Ahmed S.

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